ABSTRACT Systemic Lupus Erythematosus (SLE or lupus) is an incurable, debilitating autoimmune disease characterized by widespread inflammation and rampant production of autoantibodies. Genetics undoubtedly contributes to the etiology of SLE, with statistically robust association studies establishing 83 independent SLE genetic risk loci. Yet, effective diagnosis, treatment, and prevention of SLE is hindered by a dearth of clear mechanistic insights into the biological significance of these genetic loci. Twenty-one of 83 independent SLE risk loci encode transcription factors, and ~90% of SLE risk loci only contain variants that are non-coding. Thus, gene regulation is a likely critical aspect of SLE genetic etiology. We therefore aim to determine the mechanistic contributions of transcription factors to SLE. In our proposal, we assess the immediate downstream biological impact of risk variants that alter the amino acid sequence of a transcription factor (IRF7 - Aim 1), multiple risk variants that alter the genomic binding sites of a second transcription factor (SPI1/PU.1 - Aim 2), and examine cooperative control of gene expression by these two proteins (Aim 3). We also use innovative new mouse strains and experimental lupus models to explore the role of both factors in disease pathogenesis (Aim 3). In Aim 1, we endeavor to identify why the genotype at position 412 in interferon regulatory factor-7 (IRF7) changes the functional response of cells to intracellular signals, including those from toll-like receptors. These data will be important rationale for the development of Q412-specific inhibitors of IRF7 as novel therapeutics in SLE. In Aim 2, we build on our finding that the transcription factor SPI1/PU.1 binds at or near SLE risk loci much more than expected by chance in numerous cell types, including natural killer (NK) cells. Recent data globally link NK cell dysfunction to lupus risk, and support the burgeoning view that NK cells represent important new targets for therapeutic interventions. We leverage our NK cell expertise and these exciting new data to test the hypothesis that PU.1 binding is altered at multiple lupus genetic risk loci, leading to dysregulated expression of target genes in NK cells from SLE patients. In Aim 3, we use innovative mouse strains harboring an SLE risk- associated variant of IRF7 or NK-cell-restricted deficiency of PU.1 to determine the pathogenic roles of these transcription factors in the development of lupus. We also examine molecular interaction of PU.1 and IRF7 at composite DNA binding elements in the genome of NK cells, where these two factors may cooperatively bind, regulate gene expression, and promote disease. Our proposal leverages collaborative, conceptual, and methodological innovation to make meaningful progress towards the understanding of the independent and potentially combinatorial molecular mechanisms by which two different transcription factors intersect with SLE risk loci to promote disease.